Increased PD-L1 Restricts Liver Injury in Nonalcoholic Fatty Liver Disease

Abstract

PD-L1 is a critical checkpoint that protects tissues from autoimmune injury. Nevertheless, the role of PD-L1 in nonalcoholic fatty liver disease- (NAFLD-) induced liver damage is still unclear. In this study, we examined the role and mechanism of PD-L1 expression on NAFLD-induced liver damage in vitro and in vivo. PD-L1 expression in the livers from patients with NAFLD, and LO2 cells treated by FFA, was significantly increased. FFA triggers a large amount of ROS (generated from NOX4 and damaged mitochondria), promoting the ZNF24 expression and suppressing ZN24 sumoylation, both of which enhance the PD-L1 transcription and expression. The knockdown of PD-L1 increases CD8 + T cells' damage to FFA-treated LO2 cells, while its upregulation limits the liver injury in NAFLD models. Collectively, we demonstrate that FFA promotes PD-L1 expression through the ROS/ZNF24 pathway and suppresses UBE2I-mediated ZNF24 sumoylation to enhance its transcriptional activity of PD-L1. PD-L1 upregulation limits FFA-induced injury of hepatocytes in vitro and in vivo.